1. Technical Field
The present invention relates to vaccine therapy for cancer patients and patients having persistent lesions, such as infections. More specifically, the present invention relates to a vaccine immunotherapy that immunizes patients, having immune suppression, to both endogenous and exogenous tumor peptides or proteins, as well as those derived from other persistent lesions.
2. Background Art
It has become increasingly apparent that human cancers have antigens, which, if reacted upon by the host's immune systems, lead to tumor regression. These antigens have been defined by both serological and cellular immune approaches. This has led to the definition of both B and T cell epitopes (Sahin, U, et al., Curr Opin Immunol, 9:709-715 (1997); Van der Eynde, B, et al., Curr Opin Immunol, 9:684-693 (1997); Wang, R F, et al., Immunologic Reviews, 170:85-100 (1999)). Based upon these results, it has become a goal of cancer immunotherapists to induce regressions of tumors. However, historically, successful efforts have been sporadic and generally minor in frequency and magnitude.
A fundamental problem in the effort to immunize cancer patients is that the tumor-bearing state is associated with immunosuppressive mechanisms derived from both the tumor and the host's disturbed immune system (Kavanaugh, D Y, et al., Hematol-Oncol Clinics of North Amer., 10(4):927-951 (1996)), thereby making immunization difficult, and until now, impossible on a consistent basis. Immune suppression or depletion involves a reduced capacity of the immune system to respond. Such suppression can be drug or disease induced. The condition can be drug induced by treatment, virus induced as in AIDS, or induced by a disease state such as cancer. The immune system in this condition is effectively turned off.
A variety of tumor immunization strategies have been developed. However, all of these strategies are complex and deviate significantly from the conventional immunization strategies used for infectious diseases (Weber, J Tumor Medscape Anthology, 3:2 (2000)). One such tumor immunization strategy involves Theratope®, a Sialyl TN polysaccharide mucin antigen conjugated with keyhole limpet hemocyanine and administered with Detox® mycobacterium adjuvant and low dose cyclophosphamide (Maclean G D, et al., J Immunother Emphasis Tumor Immunol., 19(4):309-316 (1996)). However, use of this vaccine in patients with metastatic breast and ovarian cancers has yielded major clinical responses in a low percentage of patients. A major response means greater than 50% tumor reduction.
Gene therapy also has been attempted using an adenovirus construct as an expression vector for genes expressing Papilloma virus. Peptide 16 has been used for immunization for patients with cervical cancer and has yielded major clinical responses in a low percentage of patients (Borysiewickz, L K, et al., Lancet, 347:1524-1527 (1996)).
Dendritic cell mediated therapy also has been attempted, wherein dendritic cells were pulsed with oligopeptide fragments of prostate specific antigens (PSA). Prostate specific membrane antigen (PSMA) has been used in patients with metastatic prostate cancer with major clinical responses in a low percentage of patients (Sanda, M G, et al., Urology, 52:2 (1999); Murphy, G P, et al., The Prostate, 38:43-78 (1999)).
Additionally, autologous tumors have been used with low dose cyclophosphamide and BCG to immunize cancer patients with malignant melanoma. However, few clinical responses were reported (Mastrangelo M J, et al., Seminars in Oncology, 23(6):773-781 (1996)). Another strategy attempted included using MAGE antigens with a variety of vaccine adjuvants. Again, this has yielded few, if any, responses in patients with malignant melanoma.
Several U.S. patents to Doyle, et al., (U.S. Pat. Nos. 5,503,841; 5,800,810; 6,060,068; 5,643,565; 5,100,664) disclose methods of enhancing the immune response in patients using Interleukin-2 (IL-2). This method is disclosed for use in response to infectious diseases and primarily functions using antigens known to be immunogenic. Limited applicability was demonstrated. As disclosed above, the treatment of cancer is known to require different approaches. To date, treatment with IL-2 has shown minor effects in two cancers, renal cell and malignant melanoma (response rates less than 20%). It is generally considered ineffective in squamous cell head and neck cancer, cervical cancer, and in prostate cancer. Hence, it is not approved for these uses. It would therefore not be within the skill of one in the art to apply the method of the Doyle, et al. patents to the use of small peptides in the treatment of cancer.
It is important to contrast prevention with known “classic” antigens of complex structure and high molecular weights in healthy patients versus treatment (generally unsuccessful) with tumor antigens or peptides (generally unsuccessful) in immunosuppressed patients (generally unsuccessful). The first is easy and current viral vaccines attest to their efficacy. The latter is nearly impossible on a routine basis despite 30 years of intense effort.
It is important that this invention relates to, but not exclusively to, immunizing with endogenous peptide processed and presented by dendritic cells or endogenously administered to an environment (lymph node) where dendritic cells have been prepared and can present them to T cells effectively. This goal is considered by many immunologists to be insurmountable. Peptides are much too small to be effective immunogens, their half-life is short, they are often nonmutated self-antigens to which the patient is immunologically tolerant, and gaining a response is tantamount to inducing autoimmunity.
In several of the above strategies, cellular and/or tumoral immunity to tumor-associated antigens has been induced (Weber, J Tumor Medscape Anthology, 3:2 (2000); Maclean, G D, et al., J Immunother Emphasis Tumor Immunol, 19(4):309-316 (1996); Borysiewickz, L K, et al., Lancet, 347:1524-1527 (1996); Sanda, M G, et al., Urology, 52:2 (1999)). This is especially so in association with tumor regression. Nevertheless, the success rate of such treatments is negligible and inconsistent (<30%).
It would therefore be useful to develop a consistent and effective method of immunizing cancer patients.